Polyethoxylated castor oil, providing different grade “Cremophors”, have been employed as effective solvents or carriers for pharmaceuticals. For example, Cremophor EL is known for its use with an extensive array of pharmaceuticals including Miconazole (Handbook on Injectable Drugs), echinomycin (Handbook on Injectable Drugs), teniposide (Rowinsky et al. 1992, Seminars in Oncology, 19, 646), diazepam (Lau et al. 1989, Int. J. Pharm. 54, 171), althesin (Dye et al., 1980, Br. Med. J. 230, 1353) and taxol (Rowinsky et al., 1992, supra).
With its unique mechanism of action as a stabilizer of tubulin polymerization, paclitaxel (Taxol®) has become an important agent in current cancer chemotherapy. One problem associated with its clinical use has been the frequent presence of acute hypersensitivity reactions, characterized by dyspnea, flushing, rash, chest pain, tachycardia, hypotension, angioedema and generalized urticaria (Wiernic, P H et al., 1987, J Clin Oncol., 5, 1232; Wiernic, P H et al., 1987, Cancer Res., 47, 2486; Rowinsky, E K et al., 1992, Semin. Oncol., 19, 646; Bristol-Myers Squibb Oncology Products Division, Princeton, N.J. Paxitaxel (Taxol) package insert, 1993; Rowinsky, E K, 1993, Monogr. Natl. Cancer Inst. 15, 25; Rowinsky, E K et al., 1993, Semin. Oncol., 20, 1; Rowinsky, E K and Donehower, R C., 1993, Semin. Oncol. 20, 16; Sharma, A et al., 1993, Cancer Res. 53, 5877; Rowinsky, E K et al., 1994, Ann. Oncol., 5, S7; Guchelaar, H J et al., 1994, Clin. Oncol. 6, 40; Essayan, D M et al. 1996, J. Allergy Clin. Immunol. 97, 42). All documents cited herein supra and infra are hereby incorporated in their entirety by reference thereto. As a consequence of the death of a patient after being treated with paclitaxel during one of the initial clinical trials, it has become standard practice to administer this drug to patients in a 24-hour infusion after premedicating them with high-dose corticosteroids, e.g. dexamethasone, H1 antagonist antihistamines e.g. diphenhydramine, and H2 antagonists, e.g. cimetidine, ranitidine. Despite these preventive measures, however, phase II and III studies indicate that minor reactions (flushing and rash) occur in 41-44% of all patients, and that major reactions, necessitating discontinuation of paclitaxel with appropriate first-aid, may occur in approximately 1.5 to 3% of patients (Weiss, R B et al., 1990, J. Clin. Oncol. 8, 1263; Eisenhauer, E A et al., 1994, J. Clin. Oncol. 12, 2654).
The mechanism of induction of hypersensitivity reactions in response to paclitaxel administration has not yet been elucidated, and research in this area has generated an ongoing debate on the phenomenon. In particular, there is no consensus in the literature regarding two questions: 1) whether the reaction is due to paclitaxel or to the vehicle, Cremophor EL, and 2) whether the phenomenon represents an immunoglobulin E (IgE)-mediated classical type 1 allergic reaction, or it arises as a consequence of direct drug effect on mast cells and/or basophils, causing massive histamine release.
Hypersensitivity reactions to Taxol have been a long-standing concern that exclude some 2% of cancer patients from continuing to receive the drug, while necessitating high-dose steroid and antihistamine pretreatment for the rest of patients who receive this therapy. At present there is no known way to predict the reaction in new patients, or to prevent or control it through specific therapy.
Therefore, a recent report by Essayan et al. (1996, J. Allergy Clin. Immunol., 97, 42) on the prevention of Taxol-induced severe hypersensitivity reactions in a patient by a desensitization protocol similar to that pursued in β-lactam allergy, represents a possible approach to solve this problem. Nevertheless, the immune pathomechanism of hypersensitivity to Taxol and the individual roles that paclitaxel and Cremophor EL play in the reaction remain obscure.
Concerning the pathomechanism, the reaction to Taxol has been referred to in some studies as type I hypersensitivity (Weiss et al., 1990, supra; O'Brien, M. E. R. and Souberbielle, B. E., 1992, Ann. Clin. Oncol. 3, 605) primarily on the basis of its rapid clinical course and symptoms. However, conclusive evidence for a role of IgE has never been provided (Essayan et al., 1996, supra; Weiss et al. 1990, supra), and in fact, the phenomenon does not fit into the category of type I allergic reactions because most reactions to Taxol occur during the first treatment, while prior sensitization to an antigen is generally necessary for an IgE response (Rowinsky et al., 1993, supra; Weiss et al., 1990, supra). Also, the high frequency of the mild form of the reaction (41-44%) in the face of the “relative paucity of reactive groups” on paclitaxel (Essayan et al., 1996, supra) is unusual for an IgE-mediated type I reaction. The prevailing view is therefore that the reaction is multifaceted and it is unlikely to be mediated solely by IgE (Rowinsky et al., 1993, supra; Essayan et al., 1996, supra; Weiss et al., 1990, supra). However, the only alternative hypothesis at present, on a direct drug effect on basophils and/or mast cells, still lacks conclusive evidence (Decort, G. et al., 1996, Anticancer Res. 16, 317).
The individual roles of paclitaxel and Cremophor EL in the reaction are also a subject of debate. The argument that the phenomenon is due to Cremophor® EL is based on observations that it can cause hypersensitivity reaction in dogs (Lorenz, W. et al., 1977, Agents Actions 7, 63) and humans (Sharma et al., 1993, supra; Dye, D. and Watkins, J., 1980, Br. Med. J. 280, 1353; Howrie, D. L. et al., 1985, Drug Intell. Clin. Pharm. 19, 425; Lassus, M. et al., 1985, Proc. Annu. Meet. Am. Soc. Clin. Oncol. 4, 268; Nolte, H. et al. 1988, Am. J. Ped. Hematol-Oncol. 10, 308; Peereboom, D. M. et al., 1993, J. Clin. Oncol. 11, 885; Theis, J. G. et al., 1995, J. Clin. Oncol. 13, 2508; Fossells, F. V. et al., 1995, Semin. Oncol. 22, 22; Mounier, P. et al., 1995, Therapy 50, 571). However, other authors, most recently Essayan et al. (1996, supra) contradicted this view and pointed to paclitaxel as the offender.
Similarly, numerous clinical studies in recent years have been performed with liposomal formulations of anticancer drugs and other therapeutic agents. These studies attest to the general safety of i.v. liposomes, as four liposomal drugs entrapping doxorubicin (Doxil®), daunorubicin (DaunoXome®) and amphotericin B (Abelcet® and Ambisome®) are already licensed in several countries, and many others are in advanced clinical trials (Allen, T. M., 1997, Drugs 54, 8). Nevertheless, some of the studies (Sculier, J. P. et al., 1986, J. Clin. Oncol. 4, 789; Levine, S. J. et al., 1991, Annals Int. Med. 114, 664; Ringden, O. et al., 1994, Lancet 344, 1156; Laing, R. B. S. et al., 1994, Lancet 344, 682; Uziely, B. et al., 1995, J. Clin. Oncol. 13, 1777; de Marie, S., 1996, Leukemia 10, S93; Dezube, B. J., 1996, In: Doxil Clinical Series, Califon, N. J. Gardiner-Caldwell SynerMed, p. 1-8; Alberts, D. S. and Garcia, D. J., 1997, Drugs 4, 30) have also revealed a hypersensitivity reaction to liposomes that develops immediately after the start of infusion, and includes symptoms of cardiopulmonary distress, such as dyspnea, tachypnea, tachycardia, hypotension, chest pain and back pain. Unlike IgE-mediated (type I) allergy, the reaction to liposomes arises at the first exposure to the drug without prior sensitization, and the symptoms usually lessen or disappear upon later treatments. Because of these unusual features, the reaction has recently been termed “pseudo-allergic” (Alberts and Garcia, 1997, supra). The frequency of such reactions among 705 patients treated with Doxil was 6.8% (Dezube, 1996, supra) which is comparable with the incidence rate reported in other liposome trials (Levine, S. J. et al., 1991, supra; Ringden et al., 1994, supra; Uziely, B. et al., 1995, supra; deMarie, S., 1996, supra; Alberts and Garcia, 1997, supra). As the mechanism of the phenomenon is not understood, it is impossible at present to anticipate or specifically treat some 0.9% of patients who develop a severe, life-threatening reaction that precludes further treatment (Dezube, 1996, supra).
It is known that certain liposomes can activate the complement system (Szebeni, J., 1998, Crit. Rev. Ther. Drug Carrier Syst. 15, 57), and that complement activation can lead to cardiovascular and pulmonary adverse responses very similar to those described above (Marceau, F. et al., 1987, Immunopharmacol. 14, 67; Hammerschmidt, D. E. et al., 1980, Lancet 3, 947; Moore, F. D., 1994, Adv. Immunol. 56, 267). Thus, we wished to test the hypothesis that complement activation plays a causal role in the cardiopulmonary reaction to i.v. liposomes. We chose the pig as animal model as an earlier study in our laboratory demonstrated that i.v. administration of cholesterol-containing liposomes in miniature pigs elicited a severe anaphylactoid reaction that was associated with intense hemodynamic changes (Wassef, N. M. et al., 1989, J. Immunol. 143, 2990). It was proposed that the reaction was due to complement activation, however, direct, conclusive evidence regarding the causal role of complement was not available previously.
Therefore, there is a need to determine the mechanism behind the hypersensitivity reactions described above such that a method for inhibiting said hypersensitivity can be applied.